Allele Receives Tissue Bank License for Manufacturing and Distribution of cGMP-compliant iPSCs

Allele Biotechnology & Pharmaceuticals has received a Tissue Bank License from the California Department of Public Health, making it the world’s first establishment to collect tissue for the manufacture and banking of induced pluripotent stem cells (iPSCs) for commercial applications.

Allele’s cGMP facility is dedicated to the generation, banking, and differentiation of iPSCs for therapeutic use and drug discovery. All tissues and cells are processed in a state-of-the-art cleanroom to satisfy FDA requirements for Phase III clinical trials and commercial production. The cleanroom’s modular space and adaptable design allow different areas to be dedicated to the manufacture of various iPSC-derived cells.

The first tissues were processed in August 2017 when the cGMP manufacturing suite officially opened after a 2-year construction and remodeling effort and nearly a decade of iPSC reprogramming research and optimization. The iPSCs generation process is fully cGMP- and GTP-compliant, beginning with the onsite collection of tissue from donors or clients by a physician. All cGMP manufacturing personnel have undergone extensive training with strict qualification and documentation measures to ensure successful reprogramming of cells in an ISO-5 environment. Once generated, iPSCs are banked and can be distributed or differentiated for transplantation into patients. The entire process is validated and performed under the umbrella of a 21 CFR-compliant quality system.

Generation of iPSCs is based on Allele’s proprietary mRNA-only protocol which was designed and optimized expressly for cGMP production. The methods were developed to produce iPSCs that are free from genomic integration of plasmid DNA, viruses, and feeder cells. According to CEO and the lead scientist behind the technology, Dr. Jiwu Wang, “The powerful mRNA technology developed by Allele’s researchers made it much easier for cells to enter clinical trials down the road and we expect multiple patent issuances shortly.”

The cGMP facility has a dedicated mRNA production area for the manufacture of cGMP-compliant mRNAs. In addition to supporting iPSC reprogramming efforts, cGMP mRNA will support ongoing internal development programs to generate iPSC derived cells. Current efforts are focused on the development of pancreatic beta cells, neurons, oligodendrocytes and their progenitor cells, hepatocytes, muscle cells, and mesenchymal cells.

Established in 1999, Allele Biotechnology has a mission to further therapeutic innovation by providing cutting edge technologies and clinical grade solutions to partners working in collaborative and creative ways to support preclinical studies and clinical trials in the stem cell therapy arena.

Roundtable on cGMP Stem Cell Manufacturing

Allele Biotechnology & Pharmaceuticals is hosting a cGMP Stem Cell Manufacturing Roundtable to discuss ways to accelerate stem cell-based therapies toward clinical development and commercialization. The roundtable will bring together top minds from academic settings, cGMP facilities, and biotech industries in an informal setting to explore partnerships and avenues for developing effective and marketable iPSC-derived therapies.

The meeting will be held on April 20th at The Hilton on Torrey Pines and will consist of four sessions covering (1) existing cGMP facilities, (2) manufacturing and quality systems, (3) regulatory concerns, and (4) business strategy.

Meeting highlights will be produced to summarize the presentations and discussions. For inquiries, contact info@allelebiotech.com or call 858-587-6645.

Allele Publication Explains cGMP Generation of Induced Pluripotent Stem Cells

The discovery that adult somatic cells can be reprogrammed to pluripotent stem cells has given the biomedical community a powerful platform for personalized medicine. However, the translation of cell therapies from bench to bedside holds a significant challenge. Realizing the clinical potential for stem cells requires their production under current Good Manufacturing Practice (cGMP) regulations enforced by the FDA. A new protocol (http://onlinelibrary.wiley.com/doi/10.1002/cpsc.18/abstract) published by scientists at Allele and detailed in this quarter’s issue of Current Protocols in Stem Cell Biology, reveals key conditions required for converting adult fibroblasts to induced pluripotent stem cells (iPSCs) under cGMP regulations.¹

The patent-pending protocol is an update to a previous protocol that describes how to reprogram fibroblasts to iPSCs using mRNA. “The system of using mRNA to reprogram fibroblasts presents itself as a very favorable candidate for generating iPSCs for cell therapy” according to the senior author of the paper and CEO of Allele, Dr. Jiwu Wang, “our company is committed to developing stem cell based therapies using this protocol and through the establishment of our own stem cell GMP facilities here in California”. mRNA transfection is “footprint free”, meaning no insertions or alterations have been made to the genome. Transfection of mRNA is also “cleanup free,” because mRNA transcripts are supplied to the cells in the culture medium only for the time required to induce pluripotency. Furthermore, genomic analyses of iPSCs reprogrammed using mRNA indicate that this method of conversion is unlikely to introduce problematic mutations.²

The new version of the protocol describes reprogramming technology that utilizes all cGMP-certified reagents and vessels, meaning that every material is manufactured under guidelines that allow for ancillary use in manufacturing processes related to cell therapy. All materials described in the protocol – from cell medium and components to the coating for tissue culture plates – were meticulously evaluated at every step of generating and storing iPSCs. For truly cGMP produced cell lines, all processes should take place in certified cleanrooms with qualified equipment and thoroughly trained operators.

Establishing a cGMP process for any product intended for human use is a daunting undertaking. Unlike drugs and small-molecule pharmaceuticals, stem cells are living entities whose production cannot be chemically synthesized. Therefore, special considerations must be made – particularly for making individual cell lines – to help assure the highest safety and quality of downstream stem cell products. Adhering to cGMP regulations infuses high quality into the design and manufacturing process at every step. Through rigorous testing, researchers at Allele have identified critical parameters for generating iPSCs from fibroblasts that are cGMP-compliant, and are optimistic that the methods described in this recent publication will serve as a launch pad for the development of future cell products and therapies.

1. Ni Y, Zhao Y, Warren L, Higginbotham J, Wang J. cGMP Generation of Human Induced Pluripotent Stem Cells with Messenger RNA. Current Protocols in Stem Cell Biology,2016; 39:4A.6.1-4A.6.25.
2. Bhutani K, Nazor KL, Williams R, et al. Whole-genome mutational burden analysis of three pluripotency induction methods. Nature communications. 2016;7:10536.

Allele GMP CRO and Cell Therapy

Tags: Allele Therapeutics, CA company, CIRM, GMP, iPSC, stem cell therapy

Allele Receives NIH Award to Fund the Development of Large-Scale Stem Cell Production

SAN DIEGO–(BUSINESS WIRE)–

The NIH’s National Heart, Lung, and Blood Institute has awarded Allele Biotechnology and Pharmaceuticals (“Allele”) a Phase 1 SBIR grant to develop a novel manufacturing system to produce stem cell-derived human tissue and cells for clinical therapy. By increasing the scale of production and reducing the cost of manufacturing, Allele is confident that this system will overcome a considerable roadblock for clinical applications of stem cells, which is to produce a sufficient amount of therapeutic material at a manageable cost.

At the core of translating this potentially game-changing technology into medically-beneficial applications is the use of induced pluripotent stem cells (iPSCs), which hold unprecedented promise of providing any type of immune-matched cells of unlimited quantity. Allele has already developed a patented method of reprogramming somatic cells into iPSCs, secured industrial licensees using this technology, and initiated cGMP procedures for clinical applications.

Further moving iPSCs into commercially viable clinical cell therapies still requires overcoming one major barrier: the prohibitive cost of manufacturing iPSC-derived cells, mostly due to the need of expensive clinical-grade growth factors and cytokines. For example, the estimated cost of the growth factors and cytokines needed to produce a typical transfusion of platelets is $87,252.

Ultimately, Allele’s goal is to create clinical-grade iPSCs and control their differentiation into specific cell types at a scale large enough to satisfy the clinical demand. “We have been diligently working on removing the use of protein factors through our own proprietary protocols to generate many clinically-relevant cell types, including beta cells, mesenchymal stem cells, neural progenitor cells, oligodendrocytes, liver, and heart cells,” said Dr. Jiwu Wang, Allele’s CEO and the Principle Investigator of the new NIH grant. “By developing a recombinant protein-independent, real-time adjusted culture system under this project, we are confident that—as many groundbreaking technologies such as genome sequencing have done—the manufacturing process will mature and the costs will come down to eventually benefit everybody.”

Allele’s plan gained trust from the NIH scientific review panel, which gave it a near-perfect score. With this funding, Allele’s researchers will move even faster towards the goal of bringing iPSC products to clinical applications. Successful efforts will also likely provide a vehicle for genome-editing technologies such as CRISPR to be delivered into patients.

View source version on businesswire.com.

Stem Cell Therapies: What’s Approved, What Isn’t, and Why Not?

With acceptance of stem cell therapies growing, so have controversies surrounding regulations.

Desperate to heal sports injuries, top professional athletes have been known to pay tens of thousands of dollars for experimental stem cell treatments that many used to find controversial. But now, stem cell therapies have become more mainstream and are no longer limited to professional athletes. Stem cell clinics offer both medical and non-medical treatments with claims of improving aesthetics and quality of life.

One recent study found over 400 websites – with the largest portion in the United States – advertising stem cell-based therapies (1); another found over 570 U.S. clinics offering stem cell interventions (2), giving more evidence that the market for stem cell therapies in the U.S. is growing at an accelerated rate. Yet these therapies are too often based on unfounded claims and lack proper clinical trials or authorized regulation. Despite what some clinics claim, very few stem cell treatments are currently available that are actually approved by the Food and Drug Administration (FDA). Hematopoietic stem cells harvested from bone marrow are routinely used in transplant procedures to treat patients with cancer or other blood or immune system disorders. Banking of umbilical cord blood is FDA-regulated and its use is approved for certain indications. Otherwise, consumers should be wary of claims by stem cell clinics implying FDA-approval.

So why aren’t more FDA-approved stem cell therapies available?

The FDA has strict regulations on using stem cell products in humans. In most cases, stem cell-based products are categorized the same way as pharmaceutical drugs. Therefore, each new therapy must go through a rigorous process including pre-clinical animal trials, phased clinical studies, and pre-market review by the FDA prior to offering the treatment in the clinic.

And with stringent regulatory requirements comes prohibitive costs. Research animals, Phase I-III clinical trials, and the regulatory demands for good manufacturing practice (GMP) labs result in an extraordinarily costly process that may hinder the progress of new therapies. The cost of developing a new drug has even been estimated to reach billions of dollars.

Nevertheless, a complete lack of regulation of stem cell therapies – as is seen in many of the stem cell clinics springing up worldwide – is clearly problematic. Alarmingly, many clinics advertise claims related to medical diseases for which there is no scientific consensus that supports their safety or efficacy. Premature commercialization of unproven therapies not only puts patients at risk, but also jeopardizes the credibility of still-developing stem cell products.

One of the most exciting outlooks for stem cell therapy is the prospect of using one’s own stem cells for personalized medicine. Should the development of an autologous stem cell product really be regulated the same way as a pharmaceutical drug, which is aimed at treating huge populations of people? If not, how should stem cell products be regulated?

In an effort to make the transition of novel stem cell products to the clinic more seamless, some countries have made significant changes in regulations. For instance, in 2014, Japan broke out a separate regulatory system for stem cell products that softened legislation dramatically to require only limited safety and efficacy data. Some argue that countries with softer regulations and less stringent safety and efficacy milestones, such as Japan, have poised themselves to become the likely pioneers in the field of regenerative medicine.

Regulatory frameworks for the clinical application of stem cell products are still evolving in most countries, including the U.S. In March, the Reliable and Effective Growth for Regenerative health Options that improve Wellness (REGROW) Act was introduced to congress. This change in legislation would remove some of the regulatory hurdles that hinder the progress of biologic therapies.

Regardless, the FDA needs to establish a more reasonable regulatory system that can evaluate the safety and efficacy of stem cell products in a more efficient manner.

1.  Berger, I., et al., Global Distribution of Businesses Marketing Stem Cell-Based Interventions. Cell Stem Cell, 2016. 19(2): p. 158-62.

2.  Turner, L. and P. Knoepfler, Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry. Cell Stem Cell, 2016. 19(2): p. 154-7.